D’AMICO,WEBSTER,CAMPBELL, AND TWINE
3618
VOL.30
2- Substituted Thiobenzothiazole and Related Compounds. I. Novel Methods for the Preparation of 2,2’-Thiobis(benzothiazoles), 2-(N,N-Disubstituted amino)benzothiazoles, and Related Compounds’ JOHN J. D’AMICO, SIDNEYT. WEBSTER,ROBERTH. CAMPBELL, AND CHARLES E. TWINE Monsanto Company, Organic Chemicals Division, Rubber Chemicals Research Laboratories, Nitro, West Virginia Received February 26,1966 The reactions of 2-mercaptobenzothiazole with oxalyl chloride and 2-chlorobenzothiazole with disubstituted formamides afforded novel methods for the synthesis of 2,2’-thiobis(benzothiazo1e) (111) and 2 4 N,N-disubstituted amino)beneothiazoles, respectively. I n the latter reaction, replacing N,N-disubstituted formamide with formamide furnished 2-hydroxybenzothiazole. Depending on reaction conditions, the reaction of 2mercaptobenzothiazole with 2-chIorobenzothiazole in dimethylformamide gave exclusively I11 or 2 4 N,Ndimethy1amino)benzothiazole (1x1. The reaction of 2-mercaptobenzothiazole or its sodium salt with 2-chlorobenzothiazole or 2,5-dichlorobenzothiazole in various solvents were investigated and are discussed in terms of steric, orbital overlap, and electronic effects. Possible mechanisms and supporting infrared and ultraviolet data are discussed.
It has been reported2v3that the reaction of mercaptans with oxalyl chloride gives dialkyl dithiooxalates. We now report the reactions of this reagent with 2mercaptobenzimidazole, 2-mercaptobenzothiazole, and 2-mercaptobenzoxazole. The reaction of 2-mercaptobenzimidazole with oxalyl chloride furnished S,S’-bis(2-benzimidazolyl) 1,2-dithiooxalate (I) in 99% yield. Analysis and infrared spectra were in agreement for the proposed structure of I. The reaction of I with ethyl alcohol furnished 2mercaptobenzimidazole and ethyl oxalate in yields of 97 and 75.2%, respectively.
I11 (60.6%)
I1 (19.4%) DMSO
0
or
DMF
I11 (99%)
- i
140-150°t 5 hr.
5 hr.
I The reaction of 2-mercaptobenzothiazole with oxalyl chloride gave carbonyl bis(benzothiazo1ine-2-thione) (11) and 2,2’-thiobis(benzothiazo1e) (111) in yields of 19.4 and 80.6%, respectively. Proof of structure for I1 and I11 was based on elemental analysis, molecular weight, and infrared and ultraviolet spectra. The ultraviolet spectrum of I1 contained an absorption maximum a t 304 mp ( E 29,600). The spectra of 2mercaptobenzothiazole and its N-substituted derivatives possess maxima at 328 mp ( E 29,000), attributed -S to the -N>C=S group,4 while S-substituted derivatives absorb in the region of 275 mp ( E 21,000). Product I11 was also obtained in 99% yield by the reaction of anhydrous sodium 2-mercaptobenzothiazole with 2-chlorobenzothiazole in dimethylformamide or dimethyl sulfoxide. This reaction in dimethylformamide was studied a t different temperatures and found to be second order. The details of this kinetic study are reported in paper 11.6 (1) Presented a t 149th National Meeting of the American Chemical Society, Detroit, Mich., April 1965. (2) T. Jones, J . Chem. Soc., 96, 1904 (1908). (3) M. E. Arndt, Ber., 66, 1982 (1923). (4) H. P. Koch, J . Chem. Soc., 401 (1949). (5) J. J. D’Amioo, R . H. Campbell, S. T. Webster, and C. E. Twine, J . Orp. Cham., SO, 3625 (lQ65).
The reaction of 5-chloro-2-mercaptobenzothiazole with oxalyl chloride furnished only one product, 2,2’thiobis(5-chlorobenzothiazole) (IV). This same product IV was obtained in 99% yield by the reaction of anhydrous potassium 5-chloro-2-mercaptobenzothiazole with 2,5-dichlorobenzothiazole. The mechanism as illustrated in Chart I is offered for the reaction of oxalyl chloride with 2-mercaptobenzothiazole or its 5-chloro homolog. The reaction of 2-mercaptobenzoxazole with oxalyl chloride did not yield 2,2’-thiobis(benzoxazo1e) (VIII), but instead gave 2,2’-bis(benzoxazolyl) dithiocarbonate (VI) and S,S’-bis(2-benzoxazolyl) l12-dithiooxalate (VII) in yields of 41.2 and 57.5%, respectively. It is of interest that the a-diketo groups of VI1 apparently exhibited interaction. Normally, where both cis and trans configurations occur, little interaction between the carbonyls is observed in the infrared spectra. However, by using a model of this compound, it was found that if the benzoxazole rings were arranged in planar overlap, only the cis configuration of the adiketo groups existed. This would permit dipolar interactions of the keto group and lead to elevated carbonyl frequencies. The anticipated product VI11 was prepared by the reaction of the anhydrous sodium salt of 2-mercaptobenzoxazole with 2-chlorobenzoxazole. Teppema6 obtained 111 by treating 2-mercaptobenzo(6) J. Teppema, U. S. Patent 2,028,082 (1936).
%SUBSTITUTED THIOBENZOTHIAZOLE AND RELATED COMPOUNDS. 1
NOVEMBER 1965
CHARTI
I.
c1-c 4J
II
-h=o
0
1 otabilized
X
X H or C1
X
I
I
c=oJjo=c
thiazole with 2-chlorobenxothiazole in ethyl alcohol a t 25-30' for a period of 3 days. It was decided to study this reaction employing different solvents at 82-83' and the results are cited in Table I. From this
VI
VI1
DMF 140-150°, 5 hr.
(a:? N
2
VI11
study it was discovered that this was an equilibrium reaction. I n isopropyl alcohol, the equilibrium was reached in 30 min. and the yield of I11 was 72.3%. If the reaction time was extended to 3 and 5 hr., the yield of I11 was 65.5 and 56.0%, respectively. How-
*
-E
m
unstable
3619
3620
D'AMICO,WEBSTER,CAMPBELL, AND TWINE
ever, under these conditions a side reaction occurred between 2-chlorobenzothiazole and isopropyl alcohol to give the 2-isopropyloxybenzothiazole which is unstable in an acidic medium to yield 2-hydroxybenzothiazole and isopropyl chloride. Thus, the removal of 2-chlorobenzothiazole by this side reaction would explain the lowering of the yield of product I11 from 72.3 to 56% and at the same time increasing the formation of 2-hydroxybenzothiazole from 0 to 33.6% as the reaction time was extended from 30 min. to 5 hr. When decalin, a nonpolar solvent, and 1,2-bis(2methoxyethoxy)ethane, a polar solvent, were employed as the solvent, yields of 70.5 and 33.7% were obtained, respectively. However, it was anticipated that the use of 1 molar equiv. of triethylamine in an isopropyl alcohol medium would drive the equilibrium from left to right and thus increase the yield. However, this was not the case, for none of product I11 was obtained under these conditions. By the utilization of these data, an explanation of the reaction of 2-mercaptobenzothiazole with 2chlorobenzothiazole in different solvents is presented.
isopropyl alcohol in a mole ratio of 1: 1, gave the following yields based on 45.2% of unrecovered 111: 2chlorobenzothiazole, 7.5%; 2-rnercaptobenzothiazolel 69.2%; and 2-hydroxybenzothiazole, 40.3%. The following mechanism is offered to explain this reaction. H@ Cl" alcohol, 82-83', 5 hr.
+
It was anticipated that the following three reactions would have yielded only one product, 2-(5-chlorobenzothiazolyl) thiobenzothiazole (V). However, this was not the case, for 111, IV, and V were obtained in the yields shown. An attempt to separate 111, IV, and V RSNa
transition state
Steric Effect and Orbital Overlap.-Thus, in the transition state, the benzothiazolyl group would be perpendicular to the line described by the incoming nucleophile, the sp2carbon, and the leaving nucleophile. If this is the case, there should be less interference with the incoming nucleophile and the leaving nucleophile than if this carbon were an sp3. Concerning the orbital overlap, the s orbital of hydrogen could overlap with the p orbital of chlorine. This interaction constitutes partial bond formation between hydrogen and chlorine, helping to stabilize the transition state, and thus speeding up substitution. Electronic Eff ect.-Owing to the resulting increase in mutual coulombic attraction, reactions of thiobenzothiazole anions with neutral substrates are facilitated by effects leading to withdrawal of electrons from the substitution site. I n our case, this resulted from protonation of the nitrogen. As a consequence, one would expect a marked difference in reactivity between nonpolar decalin with low proton affinity, and easily protonated polar 1,2-bis(2-methoxyethoxy)ethane. As noted above, such was actually the case, for when the solvent was changed from decalin to l12-bis(2-methoxyeth0xy)ethane the yield of I11 dropped from 70.5 to only 33.7%. These results indicate the relative ease of protonation of the nitrogen varies inversely with the solvent competition for the proton. As a corollary of this concept, the reaction should be inhibited by strongly basic solvents which would form a salt with 2-mercaptobenzothiazole and thus prevent protonation. Again this was confirmed, for no I11 was obtained with triethylamine-isopropyl alcohol as the solvent. A study of the reversible reaction, that is, the reaction of I11 with hydrogen chloride dissolved in
VOL.30
R'SH
+ RCl
DMF + R'C1 w
-
I11
15O-16OoP 34.4% 5 hr.
isopropyl alcohol
I11 14.7%
82-83', 30 min.
RSR
+ R'SH-+. D M F
I11 50.0%
110-120's 5 hr.
+ + +
IV 22.6% IV 13.1% IV 30.4%
+ + +
V (1) 36.4% V (2) 2.2% V (3) 19.6%
by recrystallization was not successful. Compound V was identified from a mixture of 111, IV, and V. The mixture was separated by vapor phase chromatography. Each component was trapped at the outlet tube of the chromatograph. Infrared spectra of each indicated that the first and third chromatographic peaks were I11 and IV, respectively, while the infrared spectrum of the second peak could be accounted for as a composite of the infrared spectra of I11 and IV. Furthermore, the order of elution time from g.1.p.c. is consistent with the proposed structures. I n order to elucidate the mechanism for the above three reactions, reactions 4 and 5 were attempted and, as noted, no reaction occurred under these conditions. RSR
DMF + R'SR' 150-160°,
no reaction
(4)
+ R'C1 -ineat
no reaction
(5)
,+i
5 hr.
RSR
150-160°, b hr.
The mechanism illustrated in Chart I1 is offered for reactions 1,2, and 3. The reaction of 2-mercaptobenzothiazole with 2chlorobenzothiazole in dimethylformamide was studied and, depending on reaction conditions, either I11 or 2-(N1N-dimethylamino)benzothiazole (IX) was obtained (Table 11).
NOVEMBER 1965
2-SUBSTITUTED
THIOBENZOTHIAZOLE AND RELATED COMPOUNDS. 1
3621
TABLF, I1 ~,~'-THIOBIS(BENZOTHIAZOLE) (111) AND 2-(N,N-DIMETHYLAMINO)BENZOTHIAZOLE (Ix) Mole ratio MBT: 9-ClBT
Compd.
Temp., OC.
Time, hr.
% yield of crude
-V.p.c. I11
(wt. 7%) of crudeIX 2-C1BT
M.p., OC.
Formula
-%NCalcd.
-%S-
Found
54.30 100.0 ... . . . 101-102' ClaHsNzSs 9.33 9.13 I11 77.1' 97.4 . . . 2.6 101-102' ClaHaN&a 9.33 9.15 I11 68.5" 81.4 . . . 18.6 101-102' ClaHsNzS3 9.33 9.16 I11 and 12.9" IX 1:l 150-160 5 75.80 22.3 77.7 .. 92-93' CgHloNzS 15.72 15.50 IX 1:2 150-160 5 95.5 . . . 100.0 . . . 92-93* CgHioNzS 15.72 15.30 Based on weight of I11 (total wt. X wt. % of 111). ,Recrystallization from ethyl alcohol. c Based on weight of wt. % of IX). d Four recrystallizations from ethyl alcohol were necessary to obtain IX. I11
80-90 80-90 80-90
1:l 1:l 1:2
5 24 5
Calcd.
Found
32.03 32.03 32.03
31.78 31.94 32.02
17.99 17.80 17.99 17.88 IX (total wt. X
CHARTI1
ai
S
c-s-c'
+
\\
e
>J;(clsH
N
A
C
pj
P
c1
same process is repeated using
1I
as nucleophile
Proof of structure for IX was established by the reaction of 2-chlorobenzothiazole with either dimethylamine or excess dimethylformamide as illustrated by the following reactions. I n order to ascertain that IX
1
a > C C l
4-
25-40'
(CHhNH
It appeared desirable to study the reaction of other disubstituted formamides with 2-chlorobenzothiazoles and thus determine whether this route would be a general method for the synthesis of 2-(N,N-disubstituted amino)benzothiazoles. As noted in Table 111, yields of 97.5 to 99.5% were obtained by the reaction of 2-chlorobenzothiazole with formylmorpholine or formylhexamethylenimine, respectively. The low yield obtained with dibutylformamide was probably due t o losses occurring during distillation. However, it should be mentioned that Coppinger' was the first to report that the reaction of benzyl chloride with dimethylformamide at 150" afforded a mixture of dimethylbenzylamine and methyldibenzylamine in low yields. It was anticipated that the reaction of 2-chlorobenzothiazole with formamide would yield 2-aminobenzothiazole. However, this was not the case, for the product isolated in 90% yield was 2-hydroxybenzothiazole. Bredereck and co-workers* reported that alkyl halides reacted with formamide to give formylamino compounds or formates. They also stated that the course of the reaction depends upon the structure of the alkyl halide and is predictable and related to the
IX (98.5%"
N
lS3;;6O0, 5 hr.
M
r
l@
- HCI
(89.5%)
was not formed by the reaction of 2-mercaptobenzothiazole with dimethylformamide, an experiment was conducted employing these reactants and, as expected, 2-mercaptobenzothiazole was recovered in quantitative yield. The following mechanism is offered for the reaction of 2-chlorobenzothiazole with dimethylformamide.
H L
J
(7) G. M. Coppinger, J . A m . Chem. Soc., 76, 1372 (1954). ( 8 ) H. Bredereck, st al., Angew. Chem., 71, 753 (1969).
3622
D'AMICO, WEBSTER,CAMPBELL, AND TWINE
VOL.30
stability of the carbonium ion intermediate. I n our ~ not opinion, the reaction proceeds through an S N and by an S N 1 mechanism, and the following mechanism for the reaction of 2-chlorobenzothiazole with formamide is offered.
Experimental Sections
""
Analytical Methods .-Vapor phase chromatographic analyses of 111, IV, V, and I X were done with an F & M, Model 720, dual-column programmed-temperature gas chromatograph. A 0.25 in. X 2 ft. stainless steel column packed with 15Oj, SE-30 silicone rubber on Gas Chrom CL, 45-60 mesh (flow rate of helium, 100 cc./min.), was operated isothermally a t 260 and 300' and programmed from 140 to 300' a t 20°/min. All samples containing 2-mercaptobenzothiazole and 5-chloro-2-mercaptobenzothiazole were dissolved in chloroform and extracted three times with dilute sodium hydroxide solution before chromatographic analysis. Chloroform and dimethylformamide were suitable for preparation of chromatographic samples of 111, V, and I X and IV, respectively. The data were rendered quantitative by the use of p-terphenyl as an internal standard. The infrared spectra of all compounds were obtained in chloroform (5000 to 830 cm.-l) and dimethylformamide solutions (830 to 600 cm.-l), except the infrared spectra of V which was obtained from a film. A Perkin-Elmer Model 21 spectrophotometer with a sodium chloride prism was used in all cases. The ultraviolet spectra of VI, VII, and VI11 were determined in chloroform using a Cary Model 11 spectrophotometer. S,S'-Bis( 2-benzimidazolyl) 1,2-Dithiooxalate (I).-To a stirred slurry containing 90.2 g. (0.6 mole) of 2-mercaptobenzimidazole and 600 ml. of anhydrous benzene, 42 g. (0.33 mole) of oxalyl chloride was added dropwise at 50-60" over a 15-min. period. The stirred reaction mixture was heated a t reflux for 5 hr. After cooling to 5", the solid was collected by filtration and m.p. 195-197' dec., 99% yield. An atair dried at 25-30': tempt to recrystallize I from ethyl alcohol gave 2-mercaptobenzimidazole and diethyl oxalate. The infrared spectrum of I contained bands a t 3350, 1768, 1302, and 750 em.-'. Anal. Calcd. for CI~HI~N~OZSZ: N, 16.27; S, 18.62. Found: N, 15.86; S, 18.41. Proof of Structure.-A stirred slurry containing 68.9 g. (0.2 mole) and I and 100 ml. of ethyl alcohol was heated a t reflux for 4 hr. After cooling to O', the solid was collected by filtration and air dried at 25-30". 2-Mercaptobenzimidazole, m.p. 302303', was obtained in 97y0 yield. After recrystallization from ethyl alcohol the melting point remained unchanged. A mixture melting point with an authentic sample was not depressed and the infrared spectra of the two were superimposable. The filtrate was distilled to remove excess alcohol. Distillation of the residue in vacuo furnished diethyl oxalate, b.p. 96-97' (20 mm.), in 75.2% yield. The infrared spectrum of diethyl oxalate derived from this method and that of an authentic sample were superimposable. Anal. Calcd. for C7HBN1S: N, 18.65; S, 21.35. Found: N, 18.67; S, 21.33. Carbonyl Bis( benzothiazoline-2-thione)(11) and 2,2 '-Thiobis(benzothiazole) (111). Method I.-The reaction was carried out in a 1-1. three-necked flask equipped with an aqueous sodium hydroxide trap to remove hydrogen chloride and gas sample bottles to collect carbon monoxide and carbonyl sulfide. To a stirred slurry containing 66.9 g. (0.4 mole) of recrystallized 2mercaptobenzothiazole in 600 ml. of anhydrous benzene, 27.9 g. (0.22 mole) of oxalyl chloride was added dropwise at 50-60" over a period of 15 min. During the addition the color of the reaction mixture changed from yellow to brown and finally to purple. The stirred reaction mixture was heated a t reflux for 24 hr. Gas samples were taken a t 1-hr. and 5-hr. intervals. The infrared spectra of these samples were superimposable with authentic samples of carbon monoxide and carbonyl sulfide. The stirred reaction mixture was cooled to 30". The solids (14 9.) were removed by filtration and air dried a t 25-30'. 11, map. 179-180' dec., was obtained in 19.4% yield. The melting point remained unchanged after recrystallization from dimethylformamide. The infrared spectrum of I1 contained bands at 1735, 1332, 1300, 761, and 728 cm.-'. (e) All melting points were taken upon a Flsher-Johns block and are uncorrected.
NOVEMBER 1965
%SUBSTITUTED
THIOBENZOTHIAZOLE AND RELATED COMPOUNDS. 1
And. Calcd. for ClsH18N20Sa: N, 7.77; S, 35.58; mol. wt., 360.5. Found: N, 7.70; S, 35.49; mol. wt., 357.0. The filtrate was evaporated a t a maximum temperature of 30-40" at 1-2 mm. The resulting solids were added to 600 ml. of water containing 64 g. (0.4 mole) of 25% aqueous sodium hydroxide and stirred at 25-30' for 1 hr. The solids were collected by filtration, washed with water until neutral to litmus, and air dried at 25-30', giving 111, m.p. 95-97', in 80.6% yield. After recrystallization from ethyl alcohol, it melted a t 101-102'. The vapor phase chromatogram of both the crude and recrystallized sample gave only one peak. The infrared spectrum of I11 contained bands a t 1310,767, and 732 cm.-'. Anal. Calcd. for CI4HaN2Sa: N, 9.33; S, 32.03. Found: N, 9.23; S, 32.03. 111. Method I1 (Preferred Method).-A stirred mixture containing 56.7 g. (0.3 mole) of anhydrous'sodium 2-mercaptobenzothiazole, 49.9 g. (0.29 mole) of 2-chlorobenzothiazole, and 300 ml. of dimethylformamide or dimethyl sulfoxide was heated a t 140-150' for 5 hr. After cooling to 25', the reaction mixture was added to 1000 g. of ice-water containing 48 g. (0.3 mole) of 25% aqueous sodium hydroxide and stirred a t 0-10' for 1 hr. The solids were collected by filtration, washed with water until the washings were neutral to litmus, and air dried a t 45'. The crude product, m.p. 99-looo, was obtained in 99% yield from reaction in either solvent. After recrystallization from ethyl alcohol the product melted a t 101-102". A mixture melting point of product from either reaction with the product obtained from method I gave no depression and infrared spectra of the three samples were superimposable. The vapor phase chromatogram of both the crude and recrystallized samples gave only one peak. Anal. Calcd. for C1,HsN2Sa: N, 9.33; S, 32.03. Found (DMF reaction): N , 9.27; S, 32.39. Found (DMSO reaction): N, 9.35; S, 32.22. 111. Method 111.-To a stirred solution at 80" of 54 g. (0.3 mole) of 2-mercaptobenzothiazole in 300 ml. of the appropriate solvent, 50.9 g. (0.3 mole) of 2-chlorobenzothiazole was added in one portion. The stirred reaction mixture was heated a t 8283" for the time period specified in Table I and immediately added to 1000 g. of ice-water containing 48 g. (0.3 mole) of %yo aqueous sodium hydroxide. After stirring a t 0-10' for 0.5 hr., crude I11 was collected by filtration, washed with water until the washings were neutral to litmus, and air dried at 45'. The weight percentages of I11 and 2-chlorobenzothiazole in crude I11 were determined by vapor phase chromatography. To the combined filtrates, concentrated hydrochloric acid was added dropwise until pH 2-3 was obtained. The resulting precipitate was collected by filtration, washed with water until the washings were neutral to litmus, and air dried at 45'. The weight percentages of 2-mercaptobenzothiazole and 2-hydroxybenzothiazole were determined from the ultraviolet spectrum. The data are summarized in Table I. 2,2'-Thiobis(5-chlorobenzothiazole)(IV). Method 1.-To a stirred slurry containing 40.3 g. (0.2 mole) of 5-chloro-2-mercaptobenzothiazole in 500 ml. of anhydrous benzene, 14 g. (0.11 mole) of oxalyl chloride was added dropwise a t 50-60" over a 15-min. period. The stirred reaction mixture was heated a t reflux for 18 hr. After cooling to 5', the solids were collected by filtration. The wet solids were added to 600 ml. of water containing 32 g. (0.2 mole) of 25% aqueous sodium hydroxide and stirred for 1 hr. The solids were collected by filtration, washed with water until the washings were neutral to litmus, and air dried a t 25-30': m.p. 171-172", 90% yield. After recrystallization from dimethylformamide, it had m.p. 172-173". The vapor phase chromatogram of both the crude and recrystallized samples gave only one peak; the infrared spectrum of IV contained bands a t 1300, 862, and 800 em.-'. Anal. Calcd. for C14HBC12N2S3:C1, 19.20; N, 7.59; S, 26.05. Found: C1, 19.38; N, 7.40; S, 26.13. Method 11.-The procedure was identical with method I1 described for the preparation of I11 except that 72 g. (0.3 mole) of anhydrous potassium 5-chloro-2-mercaptobenzothiazole, 59.9 g. (0.29 mole) of 2,5-dichlorobenzothiazole,and 300 ml. of dimethylformamide were employed. The crude product, m.p. 165-167', was obtained in 95% yield. After recrystallization from dimethylformamide it melted a t 172-173". A mixture melting point with the product obtained from method I gave no depression and infrared spectra of the two were superimposable. The vapor phase chromatograms of both the crude and recrystallized sample gave only one peak.
3623
And. Calcd. for C14HsCl2N2Sa: C1, 19.20; N, 7.59; S, 26.05. Found: C1, 19.12; N,7.50; S,26.00. Mixture of 111, IV, and 2-( 5-Chlorobenzothiazoly1)thiobenzothiazole (V). Method 1.-A stirred mixture of 56.8 g. (0.3 mole) of anhydrous sodium 2-mercaptobenzothiazole, 50.1 g. (0.25 mole) of 2,5-dichlorobenzothiazole, and 300 ml. of dimethylformamide was heated a t 150-160' for 5 hr. After cooling to 25', the reaction mixture was added to 1000 g. of ice-water containing 48 g. (0.3 mole) of aqueous 25% sodium hydroxide. After stirring at 0-10' for 1 hr., the solid was collected by filtration and washed with water until the washings were neutral to litmus. The wet product was reslurried in 600 ml. of water containing 48 g. (0.25 mole) of 25% sodium hydroxide, filtered, washed with water until neutral, and air dried a t 45", giving 77 g. of crude product, m.p. 81-84', which contained 111, IV, and V. An attempt to resolve these compounds by recrystallization was not realized. However, this mixture was resolved by vapor phase chromatography to give 33.6, 27.0, and 39.4 wt. % and 34.4, 22.6, and 36.47, yield of 111, IV, and V, respectively. The infrared spectra of I11 and I V obtained from the vapor phase chromatogram and authentic samples of I11 and I V were superimposable. The infrared spectrum of V appeared as a composite of I11 and I V as would be anticipated and contained bands a t 1310, 1300, 862, 800, 755, and 733 em.-'. Method 11.-To a stirred solution of 60.5 g. (0.3 mole) of 5chloro-2-mercaptobenzothiazole in 400 ml. of isopropyl alcohol at go', 50.9 g. (0.3 mole) of 2-chlorobenzothiazole was added in one portion. The stirred reaction mixture was heated a t 82-83' for 30 min. and immediately added to 1000 g. of ice-water containing 48 g. (0.3 mole) of 25yo aqueous sodium hydroxide. After stirring a t 0-10' for 30 min., the solid was collected by filtration, washed with water until the washings were neutral to litmus, and air dried at 45'. The crude product (30 g.), m.p. 113-116', contained 111, IV, and V. Based on vapor phase chromatography the data in Table IV were obtained.
TABLE IV Compd.
Wt. %
% yield
111
44.3 48.3 7.4
14.7 13.1 2.2
1v V
Method 111.-A stirred solution of 30 g. (0.1 mole) of I11 and 20.2 g. (0.1 mole) of 5-chloro-2-mercaptobenzothiazole in 50 ml. of dimethylformamide was heated a t 110-120' for 5 hr. The cooled solution was added to 1000 g. of ice-water containing 32 g. (0.2 mole) of 25% aqueous sodium hydroxide and stirred a t 5-15' for 1hr. The solid was collected by filtration, washed with water until the wash water was neutral to litmus, and air dried a t 45'. The crude product (33 g.), m.p. 80-85', contained 111, IV, and V. The vapor phase chromatogram of this mixture furnished the data in Table V.
TABLE V Compd.
I11 IV V
Wt. %
45.8 34.2 20.0
% yield
50.0 (recovered) 30.4 19.6
Attempted Preparation of V. Method 1V.-A stirred solution containing 0.1 mole each of I11 and I V in 300 ml. of dimethylformamide was heated a t 150-160' for 5 hr. After cooling to 25", the solution was added to 2000 g. of ice-water and stirred at 0-10' for 1 hr. The solid was collected by filtration and air dried at 45". Based on V.P.C. data and the infrared spectrum, no reaction occurred under these conditions. V. Method V.-A stirred mixture of 20.4 g. (0.1 mole) of 2,5-dichlorobenzothiazole and 30 g. (0.1 mole) of I11 was heated V.P.C. a t 150-160' for 5 hr. and then allowed to cool to 25-30', analysis and the infrared spectrum revealed the presence of the starting reactants indicating that no reaction occurred under these conditions. 2,2'-(Benzoxazolyl) Dithiocarbonate (VI) and S,S'-Bis(2benzoxazolyl) 1,2-Dithiooxalate (VII).-To a stirred slurry of 60.4 g. (0.4 mole) of 2-mercaptobenzoxazole and 600 ml. of anhydrous benzene, 28 g. (0.22 mole) of oxalyl chloride was added dropwise a t 50-60" over a 15-min. period. The stirred reaction
3624
D'AMICO,WEBSTER,CAMPBELL, AND TWINE
mixture was heated at reflux for 24 hr. After cooling the stirred reaction mixture to 30', the precipitate (VI)was collected by filtration and air dried a t 25-30': m.p. 175-176' dec., 41.2% yield. After recrystallization from ethyl acetate-acetone, it had m.p. 176-178' dec. The infrared spectrum V I contained bands at 1738, 1278, 1252, and 756 cm.-1; the ultraviolet absorption spectra of VI displayed ' : : :A at 333 mp (e 9470) and 293 mp ( e 28,000). Anal. Calcd. for CllHsN203S2: N, 8.53; S, 19.53; mol. wt., 328.4. Found: N, 8.54; S, 19.53; mol. wt., 329. The filtrate was evaporated a t a maximum temperature of 30' a t 1-2 mm. The resulting solid (VII)was air dried a t 25-30': m .p. 131-133' dec., 57.7% yield. After recrystallization from ethyl acetate, it had m.p. 154-155' dec. The infrared spectrum of VI1 contained bands a t 1717, 1696,1278, 1262, and 756 cm.-l; at 318 the ultraviolet absorption spectra of VI1 displayed mp ( e 12,600) and 283 mp ( e 20,400). Anal. Calcd. for ClaHsNzOBz: N, 7.86; S, 18.00; mol. wt ., 356.4. Found: N, 7.92; S, 18.01; mol. wt., 349. 2,2'-Thiobis( benzoxazole) (VIII).-To a stirred solution of 37.4 g. (0.21 mole) of anhydrous sodium 2-mercaptobenzoxazole in 200 ml. of dimethylformamide, 30.7 g. (0.2 mole) of 2-chlorobenzoxazole was added in one portion. The stirred reaction mixture was heated a t 140-150" for 5 hr. After cooling to 25', the reaction mixture was added to 1000 g. of ice-water containing 31.8 g. (0.21 mole) of 25y0 aqueous sodium hydroxide. After stirring at 0-10' for 1 hr., the precipitate was collected by filtration, washed with water until the washings were neutral to litmus, and air dried at 45'. The product, m.p. 140-145", was obtained in 52% yield. After recrystallization from toluene it melted a t 160'. The infrared spectrum of VI11 contained bands at 1278,1236, and 760 cm.-l. The ultraviolet absorption spectra of VI11 displayed a t 312 mp ( e 18,600) and 285 mp ( e 25,100). Anal. Calcd. for ClaHsN202S: N, 10.44; S, 11.95; mol. wt., 268.3. Found: N, 10.35; S, 11.60; mol. wt., 276. Reaction of I11 with Alcoholic Hydrogen Chloride.-To a stirred solution of 100 ml. of isopropyl alcohol containing 3.7 g. (0.1 mole) of hydrogen chloride, 30 g. (0.1 mole) of I11 was added in one portion. The stirred solution was heated at 8283' for 5 hr. After cooling to 25', 500 ml. of water containing 32 g. (0.2 mole) of 257, aqueous sodium hydroxide was added. After stirring at 25-30' for 30 min., unreacted I11 was collected by filtration, washed with water until neutral to litmus, and air dried a t 25-30'. I11 (54.8%), m.p. 100-101", which contained 3.4 wt. % of 2-chlorobenzothiazole by vapor phase chromatography, was recovered. After recrystallization from ethyl alcohol, I11 (Anal. Calcd. for ClaHsN2Sg: N , 9.33; S, 32.03. Found: N, 9.48; S, 32.15.) melted at 101-102'. The combined filtrate was made acidic with concentrated hydrochloric acid, and the resulting precipitate was collected by filtration, washed with water until neutral to litmus, and air dried at 25-30'. The product (8 9.) melted a t 137-170'. Based on the ultraviolet spectrum this mixture contained 65 -5% 2-mercaptobenzothiazole and 34.5y0 2-hydroxybenzothiazole. After two recrystallizations from ethyl alcohol, 2-mercaptobenzothiazole, m.p. 180-181 ', was isolated. Based on 45.2% of unrecovered 111, the following yields were obtained: 2-chlorobenzothiazole, 7.5%; 2-mercaptobenzothiazole ( A n d . Calcd. for C7H6NS2: N, 8.38; S, 38.34. Found: N, 8.19; S, 38.03.), 69.2%; and 2-hydroxybenzothiazole, 40.3%. Reaction of 2-Mercaptobenzothiazole with 2-Chlorobenzothiazole in Dimethylformamide. I11 and 2-(N,N-Dimethylamino)benzothiazole (IX) ,-A stirred solution containing 0.3 mole of 2-mercaptobenzothiazole and 0.3 or 0.6 mole of 2-chlorobeneothiazole in 300 ml. of dimethylformamide was heated as described in Table 11. After cooling to 25", 700 ml. of water containing 48 g. (0.3 mole) of 25% aqueous sodium hydroxide was added. The stirred reaction mixture was maintained at 0-10" for 2 hr. The resulting solid was collected by filtration, washed with water until neutral, and air dried a t 45-50'. All recrystallized samples of I11 gave only one peak on the vapor phase chromatogram. A mixture melting point of I11 derived by this method with an authentic sample was not depressed and infrared spectra of all samples were superimposable. The infrared spectrum of Ix contained bands at 1450, 1290, 757, and 728 cm.-1. The data are summarized in Table 11. Proof of Structure of IX. Method 1.-A stirred solution of 50.9 g. (0.3 mole) of 2-chlorobenzothiazole in 300 ml. of dimethylformamide was heated a t 150-160" for 5 hr. After cooling to
VOL.30
25', 700 ml. of water containing 48 g. (0.3 mole) of 25y0 aqueous sodium hydroxide was added and stirred a t &lo' for 2 hr. The resulting solid was collected by filtration, washed with water until neutral to litmus, and air dried at 25-30'. The product, m.p. 92-93', was obtained in 89.5% yield. After recrystallization from heptane, the melting point remained unchanged. The vapor phase chromatograms of both the crude and recrystallized product gave only one peak. A mixture melting point with IX prepared above gave no depression and the infrared spectra of the two were superimposable. Anal. Calcd. for CeH10N2S: N, 15.72; S, 17.99. Found: N, 15.71; S, 18.01. Method 11.-To a stirred solution of 900 g. (5.0 moles) of 25% aqueous dimethylamine, 84.8 g. (0.5 mole) of 2-chlorobenzothiazole was added in one portion. An exothermic reaction set in causing a temperature rise from 24 to 38" over a 2-hr. period. The reaction mixture was stirred a t 25-30' for 24 hr. The resulting solid was collected by filtration, washed with water until the washings were neutral to litmus, and air dried a t 25-30'. The product, m.p. 91-92', was obtained in 98.5% yield. After recrystallization from heptane it melted a t 92-93'. A mixture melting point with products obtained from the above two methods gave no depression and the infrared spectra of the three samples were superimposable Anal. Calcd. for CsHlON2S: N, 15.72; S, 17.99. Found: N, 16.00; S, 17.98. 2-(N,N-Dimethylamino)-5-chlorobenzothiazole(X).-This reaction was carried out in the same manner as described in method I1 above except 102 g. (0.5 mole) of 2,5-dichlorobeneothiazole was employed. The crude product, m.p. 106-108', was obtained in 90.5% yield. After recrystallization from heptane it melted a t 113-114'. The infrared spectrum of X contained bands a t 1448, 1285, 862, and 803 cm.-'. Anal. Calcd. for COHoClN2S: C1, 16.67; N, 13.17; S, 15.08. Found: C1, 17.12; N, 13.11; S, 14.90. Attempted Reaction of 2-Mercaptobenzothiazole with Dimethylformamide.-A stirred solution of 85 g. (0.5 mole) of 2mercaptobenzothiazole in 200 ml. of dimethylformamide was heated a t 150-160' for 5 hr. After cooling to 25', 700 ml. of water containing 80 g. (0.5 mole) of 25% aqueous sodium hydroxide was added and stirred a t 25-30' for 30 min. To this stirred solution concentrated hydrochloric acid was added dropwise until pH 3 was reached. The resulting precipitate was collected by filtration, washed with water until the washings were neutral to litmus, and air dried a t 50'. 2-Mercaptobenzothiazole, m.p. 180-181', was recovered in quantitative yield. A mixture melting point with an authentic sample gave no depression. 2-( N,N-Disubstituted amino)benzothiazole (XI-XV). Method I. XI, XIII, and XV.-A stirred solution of 34 g. (0.2 mole) of 2-chlorobenzothiazole in 0.8 mole of the appropriate substituted formamide (Table 111) was heated a t 180-190' for 5 hr. and then cooled to 30'. For XI and XIII,700 ml. of water containing 32 g. (0.2 mole) of aqueous sodium hydroxide was added. The stirred reaction mixture was stirred at 0-10' for 1 hr. The precipitate was collected by filtration, washed with water until For XV,400 ml. of neutral to litmus, and air dried at 25-30'. water containing 32 g. (0.2 mole) of 25% aqueous sodium hydroxide and 500 ml. of ethyl ether were added and stirring was continued for 15 min. The separated ether layer was washed with water until the washings were neutral to litmus and dried over sodium sulfate. The ether was removed in vacuo a t a maximum temperature of 30'. The residue was distilled in vaeuo. The data are summarized in Table 111. Method 11. XI-XV.-To a stirred solution containing 1.5 moles of the appropriate amine in 100 ml. of water, 0.5 mole of 2-chlorobenzothiaeole or 2,5-dichlorobenzothiazole was added over a 5-min. period. An exothermic reaction occurred, causing a temperature rise from 25 to 45'. The stirred reaction mixture was heated a t 90-100' for 5 hr. and then cooled to 30". For all compounds except XV,400 g. of ice-water was added and the mixture. was stirred at 0-10' for 30 min. The resulting precipitate was collected by filtration, washed with water until neutral to litmus, and air dried a t 25-30'. For XV,400 ml. of water and 500 ml. of ethyl ether were added. The separated ether layer was washed with water until the washings were neutral to litmus and dried over sodium sulfate. The ether was removed in vacuo, and the residue was distilled in vaeuo. A mixture melting point of XI and XI11 obtained from methods I and 11, respectively,
.
2-SUBSTITUTED THIOBENZOTHIAZOLE AND RELATED COMPOUNDS. 11
NOVEMBER 1965
was not depressed and the infrared spectra were superimposable. The data are summarized in Table 111. 2-Hydroxybenzothiazo1e.-A stirred solution of 42.4 g. (0.25 mole) of 2-chlorobenzothiazole in 90.1 g. (2.0 moles) of formamide was heated at 180-190" for 5 hr. During this heating period hydrocyanic acid v a s liberated. After cooling to IO", 200 g. of ice-water was added and stirring was continued at 0-10" for 1 hr. The resulting precipitate was collected by filtration, washed with 100 ml. of cold water, and air dried a t 45". The product, m.p. 118-121', was obtained in 90% yield. After recrystallization from dilute ethyl alcohol it melted at 138-139'. A mixture
3625
melting point with an authentic sample was not depressed and the infrared spectra of the two were superimposable. Anal. Calcd. for C7H5NOS: N, 9.27; S, 21.21. Found: N, 9.44; S, 21.27.
Acknowledgment.-The authors wish to acknowledge their indebtedness to Dr. M. J. S. Dewar, Dr. W. H. Urry, Dr. N. J. Leonard, and Mr. R. 0. Zerbe for their helpful suggestions during the course of this investigation.
2-Substituted Thiobenzothiazole and Related Compounds. IL1t2 A Kinetic Study of the Reaction of 2-Chlorobenzothiazole with the Sodium Salt of 2-Mercaptobenzothiazole JOHNJ. D'AMICO,ROBERTH. CAMPBELL, SIDNEY T. WEBSTER,AND CHARLES E. TWINE Monsanto Company, Organic Chemicals Division, Rubber Chemicals Research Laboratories, Nitro, West Virginia Received February 66,1966 The kinetics of the reaction of 2-chlorobenzothiazole (I) with the sodium salt of 2-mercaptobenzothiazole (11) in dimethylformamide to yield 2,2'-thiobis(benzothiazo1e) (111) were studied. Rate constants for the reaction were determined at various temperatures. The reaction was found to be second order with an activation energy of 20.9 f 1.6 kcal. and an activation entropy of -18.0 e.u. An analytical scheme for the determination of I, 11, and I11 was developed and applied to the measurement of the rate constants. The rate constants obtained from the concentrations of I, 11, and I11 were in good agreement and eliminated the presence of possible competitive and consecutive reactions under the cited conditions.
I n order to propose a plausible mechanism for the reaction of 2-chlorobenzothiazole (I) with the sodium salt of 2-mercaptobenzothiazole (11) to yield 2,2'thiobis(benzothiazo1e) (111) and sodium chloride in part I2of this series of publications, a knowledge of the reaction order of reaction 1 was essential. a > C - C l
N
I
+a>C-S-Na
A consecutive reaction discussed in part 1116of this series involving the rearrangement of I11 to 3-(2benzothiazolyl)-2-benzothiazolinethione (reaction 2) could exist and cause erroneous conclusions.
-
S
DMF
N I1
Brower and co-workers3 reported the reaction of I with piperidine to be a second-order reaction and Lemons and co-workers4 indicated that the reaction of I with ammonia is also a second-order reaction. Gilman and co-workers5 prepared 2-ethoxybenzothiazole by the reaction of I with sodium ethoxide, but no kinetic data for the reaction were reported. The knowledge of several possible competitive and consecutive reactions made it highly desirable to follow initially all concentrations of I, 11, and 111 at higher temperatures, and to determine the extent of such interfering reactions. Evidence was given in part I2 of this series for the existence of the competitive reaction where I reacts with DMF at 150-160" to give 2- (N,N-dimethylamino) benzo thiazole in 89.5% yield. (1) Presented a t the 16th Pittsburgh Conference on Analytical Chemistry and Applied Spectroscopy, Pittsburgh. Pa., March 2, 1965. (2) Paper I: J. J. D'Amico, 9. T. Webster, R. H. Campbell, and C. E. Twine, J . Oro. Chem., 80, 2618 (1965). (3) K. R . Brower, J. W . Way, W. P. Samuels, and E. D.Amatuts, ibid., 19, 1830 (1954). (4) J. F. Lemons, R. C. Anderaon, and G. W. Watt, J . Am. Chem. Soc., 68, 1953 (1841). (5) H.Gilman, K.E. Lsnts, and J. A. Beel, ibid., 74, 1081 (1952).
W
I11
In view of these possible sources of error, it was deemed essential that any study made must be sufficiently comprehensive to detect and correct for any of these interfering reactions, if present, under the conditions selected. Therefore, specific analytical methods based on ultraviolet spectroscopy and vapor phase chromatography (v.P.c.) were developed and applied to the determination of I, 11, and I11 in DMF as described in the Experimental Section. The reaction of I with I1 was thought to involve a nucleophilic displacement of chloride ion of I ( S N ~by ) I1 anion (reaction 3). On the other hand, there was the
( 6 ) J. J. D'Amico, S. T. Webster, J . Ovu. Chem., 30, 2628 (1965).
R.
H. Campbell, and C. E. Twine,
